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1.
Age-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress. 相似文献
2.
Inhaled allergens from house dust, mites or animal danders activate human complement in vitro by engaging the C1-component
through a non-antibody-dependent mechanism. These earlier findings are extended by showing that the allergenic components
in extracts of Parietaria pollen are almost equally potent complement activators as those from house dust or mites. Spectroscopic evidence indicates
that haemolytic complement consumption by the Parietaria allergens and their enzymic fragments is most likely related to post-translational side-chains comprising flavonoid derivatives.
These adsorbed and/or peptide-bound tannin-like structures may also explain the exceptional stability of the high- and low-molecular
mass allergenic components in Parietaria pollen extracts.
Received 12 November 1996; received after revision 12 December 1996; accepted 17 December 1996 相似文献
3.
Phospholipase D (PLD) catalyses the hydrolysis of phosphatidylcholine to generate the lipid second messenger, phosphatidate
(PA) and choline. PLD activity in mammalian cells is low and is transiently stimulated upon activation by G-protein-coupled
and receptor tyrosine kinase cell surface receptors. Two mammalian PLD enzymes (PLD1 and PLD2) have been cloned and their
intracellular regulators identified as ARF and Rho proteins, protein kinase Cα as well as the lipid, phosphatidylinositol
[4, 5] bisphosphate (PIP 2). I discuss the regulation of these enzymes by cell surface receptors, their cellular localisation and the potential function
of PA as a second messenger. Evidence is presented for a role of PA in regulating the lipid kinase activity of PIP 5-kinase,
an enzyme that synthesises PIP 2. A signalling role of phospholipase D via PA and indirectly via PIP 2 in regulating membrane traffic and actin dynamics is indicated by the available data.
Received 25 April 2001; received after revision 15 June 2001; accepted 15 June 2001 相似文献
4.
The physical nature of the agent that causes transmissible spongiform encephalopathies (the 'prion'), is the subject of passionate
controversy. Investigation of it has benefited tremendously from the use of transgenic and knockout technologies. However,
prion diseases present several other enigmas, including the mechanism of brain damage and how the affinity of the agent for
the central nervous system is controlled. Here we show that such questions can be effectively addressed in transgenic and
knockout systems, and that pathogenesis may be clarified even before we can be certain about the nature of the infectious
agent. Availability of mice overexpressing the Prnp gene (which encodes the normal prion protein) and Prnp knockout mice allows for selective reconstitution experiments aimed at expressing PrP in specific portions of the brain or
in selected populations of hemato- and lymphopoietic origin. We summarize how such studies can offer insights into how prions
administered to peripheral sites can gain access to central nervous tissue, and into the molecular requirements for spongiform
brain damage. 相似文献
5.
Summary IK activity titrated by the sedimentation method in sera from patients affected with SLE was found to be negatively correlated with C4 and C3 complement factors levels. The significance of this data is discussed.Index of the abbreviations used: SLE, systemic Lupus eritematosus; IK, immunoconglutinins; CH50, Total haemolytic activity; C4b, Complement factor connect with the complex AgAbCl; C3b, Complement factor connect with the complex AgAbClC4C2; C3PA, C3 proactivator in the complement activation by the alternate pathway implicated; KAF, Conglutinogen activating factor inactive the C3b in C3c and C3d. Antrypol, factor that makes C3b KAF-unreactive. 相似文献
6.
Microtubules are fibrous elements in the cytoplasm of eukaryotic cells, where they perform a wide variety of functions. Microtubules
are major organizers of the cell interior and are vitally involved in motility events such as chromosome migration during
cell division. To fulfill their physiological function, microtubule arrays have to undergo dramatic changes in their spatial
arrangement, and this depends to a large extent on the complex and special dynamic properties of the individual polymers.
In this review we first describe the intrinsic dynamic properties of microtubules assembled in vitro from purified tubulin
and examine the relationships between these properties and microtubule functions. Subsequent sections concern microtubule
dynamics in vivo, their similarity and differences with microtubule dynamics in vitro, and the nature of the cellular regulators
which act on microtubule assemblies in physiological conditions.
Received 2 May 2001; received after revision 10 July 2001; accepted 10 July 2001 相似文献
7.
Trimeric guanine nucleotide-binding proteins (G proteins) function as the key regulatory elements in a number of transmembrane
signaling cascades where they convey information from agonist-activated receptors to effector molecules. The subcellular localization
of G proteins is directly related to their functional role, i.e., the dominant portion of the cellular pool of G proteins
resides in the plasma membrane. An intimate association of G protein subunits with the plasma membrane has been well known
for a long time. However, results of a number of independent studies published in the past decade have indicated clearly that
exposure of intact target cells to agonists results in subcellular redistribution of the cognate G proteins from plasma membranes
to the light-vesicular membrane fractions, in internalization from the cell surface into the cell interior and in transfer
from the membrane to the soluble cell fraction (high-speed supernatant), i.e., solubilization. Solubilization of G protein
α subunits as a consequence of stimulation of G protein-coupled receptors (GPCRs) with agonists has also been observed in
isolated membrane preparations. The membrane-cytosol shift of G proteins was detected even after direct activation of these
proteins by non-hydrolyzable analogues of GTP or by cholera toxin-induced ADP-ribosylation. In addition, prolonged stimulation
of GPCRs with agonists has been shown to lead to down-regulation of the relevant G proteins. Together, these data suggest
that G proteins might potentially participate in a highly complex set of events, which are generally termed desensitization
of the hormone response. Internalization, subcellular redistribution, solubilization, and down-regulation of trimeric G proteins
may thus provide an additional means (i.e., beside receptor-based mechanisms) to dampen the hormone or neurotransmitter response
after sustained (long-term) exposure.
Received 31 August 2001; received after revision 31 October 2001; accepted 7 November 2001 相似文献
8.
The pathomechanism of antibody-mediated tissue damage in autoimmune diseases can be best studied in experimental models by
passively transferring specific autoantibodies into animals. The reproduction of the disease in animals depends on several
factors, including the cross-reactivity of patient autoantibodies with the animal tissue. Here, we show that autoantibodies
from patients with epidermolysis bullosa acquisita (EBA), a subepidermal autoimmune blistering disease, recognize multiple
epitopes on murine collagen VII. Indirect immunofluorescence microscopy revealed that EBA patients’ IgG cross-reacts with
mouse skin. Overlapping, recombinant fragments of murine collagen VII were used to characterize the reactivity of EBA sera
and to map the epitopes on the murine antigen by ELISA and immunoblotting. The patients’ autoantibody binding to murine collagen
VII triggered pathogenic events as demonstrated by a complement fixing and an ex vivo granulocyte-dependent dermal–epidermal
separation assay. These findings should greatly facilitate the development of improved disease models and novel therapeutic
strategies. 相似文献
9.
Using a set of 372 proteins representative of a variety of 56 distinct globular folds, a statistical correlation was observed
between two recently revealed features of protein structures: tightened end fragments or 'closed loops', i. e. sequence fragments
that are able in three-dimensional (3D) space to nearly close their ends (a current parameter of polymer physics), and 'topohydrophobic
positions', i. e. positions always occupied in 3D space by strong hydrophobic amino acids for all members of a fold family.
Indeed, in sequence space, the distribution of preferred lengths for tightened end fragments and that for topohydrophobic
separation match. In addition to this statistically significant similarity, the extremities of these 'closed loops' may be
preferentially occupied by topohydrophobic positions, as observed on a random sample of various folds. This observation may
be of special interest for sequence comparison of distantly related proteins. It is also important for the ab initio prediction
of protein folds, considering the remarkable topological properties of topohydrophobic positions and their paramount importance
within folding nuclei. Consequently, topohydrophobic positions locking the 'closed loops' belong to the deep cores of protein
domains and might have a key role in the folding process.
Received 1 February 2001; accepted 7 February 2001 相似文献
10.
The first tetraspanins were discovered on surface of human leucocytes, but it was rapidly demonstrated that they had a wider
tissue expression. Twenty-six molecules display sufficient homology to belong to the same superfamily. Their function is not
precisely known, but data coming from biochemical studies or knockout mice suggest that they play a major role in membrane
biology. One of their outstanding properties is their ability to form a network of multimolecular complexes, the 'tetraspanin
web', in which integrins are included. The structure of these complexes is under investigation, but some of the rules that
govern their organization have already been unraveled. The challenge is to determine how the organization of the 'tetraspanin
web' modifies the function of its constitutive molecules and consequently influences cellular behaviour. The implications
may be considerable for the understanding of basic cellular processes such as migration and also of diseases related to loss
or mutation of a single tetraspanin.
Received 29 December 2000; received after revision 26 February 2001; accepted 19 March 2001 相似文献
11.
Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic diseases in humans. The discovery
that mutations in the PKD1 and PKD2 genes are responsible for ADPKD has sparked extensive research efforts into the physiological and pathogenetic role of polycystin-1
and polycystin-2, the proteins encoded by these two genes. While polycystin-1 may mediate the contact among cells or between
cells and the extracellular matrix, a lot of evidence suggests that polycystin-2 represents an endoplasmic reticulum-bound
cation channel. Cyst development has been compared to the growth of benign tumors and this view is highlighted by the model
that a somatic mutation in addition to the germline mutation is responsible for cystogenesis (two-hit model of cyst formation).
Since in vitro polycystin-1 and polycystin-2 interact through their COOH termini, the two proteins possibly act in a common
pathway, which controls the width of renal tubules. The loss of one protein may lead to a disruption of this pathway and to
the uncontrolled expansion of tubules. Our increasing knowledge of the molecular events in ADPKD has also started to be useful
in designing novel diagnostic and therapeutic strategies.
Received 12 September 2001; received after revision 7 November 2001; accepted 7 November 2001 相似文献
12.
Plant diseases caused by plant pathogenic fungi continuously threaten the sustainability of global crop production. An effective
way to study the disease-causing mechanisms of these organisms is to disrupt their genes, in both a targeted and random manner,
so as to isolate mutants exhibiting altered virulence. Although a number of techniques have been employed for such an analysis,
those based on transformation are by far the most commonly used. In filamentous fungi, the introduction of DNA by transformation
typically results in either the heterologous (illegitimate) integration or the homologous integration of the transforming
DNA into the target genome. Homologous integration permits a targeted gene disruption by replacing the wild-type allele on
the genome with a mutant allele on transforming DNA. This process has been widely used to determine the role of newly isolated
fungal genes in pathogenicity. The heterologous integration of transforming DNA causes a random process of gene disruption
(insertional mutagenesis) and has led to the isolation of many fungal mutants defective in pathogenicity. A big advantage
of insertional mutagenesis over the more traditional chemical or radiation mutagenesis procedures is that the mutated gene
is tagged by transforming DNA and can subsequently be cloned using the transforming DNA. The application of various transformation-based
techniques for fungal gene manipulation and how they have increased our understanding and appreciation of some of the most
serious plant pathogenic fungi are discussed.
Received 9 May 2001; received after revision 2 July 2001; accepted 3 July 2001 相似文献
13.
Synthetic peptides derived from the C-terminal end of the human complement serine protease C1s were analysed by circular
dichroism and nuclear magnetic resonance (NMR) spectroscopy. Circular dichroism indicates that peptides 656-673 and 653-673
are essentially unstructured in water and undergo a coil-to-helix transition in the presence of increasing concentrations
of trifluoroethanol. Two-dimensional NMR analyses performed in water/trifluoroethanol solutions provide evidence for the occurrence
of a regular α-helix extending from Trp659 to Ser668 (peptide 656-673), and from Tyr656 to Ser668 (peptide 653-673), the C-terminal segment
of both peptides remaining unstructured under the conditions used. Based on these and other observations, we propose that
the serine protease domain of C1s ends in a 13-residue α-helix (656Tyr-Ser668) followed by a five-residue C-terminal extension. The latter appears to be flexible and is probably
locked within C1s through a salt bridge involving Glu672.
Received 19 November 1997; accepted 24 November 1997 相似文献
14.
Hormones produced by the anterior pituitary gland have been implicated in the regulation of primary lymphocyte development.
In order to identify endocrine factors involved in that process, several strains of mice with genetic defects resulting in
a selective impairment in the production of one or more anterior pituitary-derived hormones have been analysed. This study
has resulted in the classification of endocrine hormones into the following four categories (i) hormones such as prolactin
with no apparent effects on primary lymphopoiesis; (ii) anabolic hormones such as growth hormone and insulin-like growth factor-I
whose stimulatory effects on primary lymphopoiesis are non-lineage-specific and related to their actions as systemic mediators
of growth and/or differentiation; (iii) hormones such as thyroid hormones that have an obligate role in primary B lymphopoiesis;
and (iv) hormones such as oestrogens that act as negative regulators of lymphopoiesis. 相似文献
15.
Summary Factors exhibiting anti-complementary activity released from trypanosomes after incubation at 20°C were described. The active material was shown to consume the first component of bovine complement. While the anticomplementary factor(s) from T. lewisi could activate bovine, human and guinea pig complement, the factor(s) from T. congolense was observed to activate bovine complement, but not guinea pig and only slightly human complement. The roles of complement activating factor(s) of trypanosomes in the pathology of the disease are discussed.This project is supported by National Research Council of Canada grant A 0068 and a grant from the International Development Research Centre. 相似文献
16.
Cardiovascular diseases involve abnormal cell-cell interactions leading to the development of atherosclerotic plaque, which
when ruptured causes massive platelet activation and thrombus formation. Parts of a loose thrombus may detach to form an embolus,
blocking circulation at a more distant point. The integrins are a family of adhesive cell receptors interacting with adhesive
proteins or with counterreceptors on other cells. There is now solid evidence that the major integrin on platelets, the fibrinogen
receptor α
IIb
β
3 , has an important role in several aspects of cardiovascular diseases and that its regulated inhibition leads to a reduction
in incidence and mortality due to these disorders. The development of α
IIb
β
3 inhibitors is an important strategy of many pharmaceutical companies which foresee a large market for the treatment of acute
conditions in surgery, the symptoms of chronic conditions and, it is hoped, maybe even the successful prophylaxis of these
conditions. Although all the associated problems have not been solved, the undoubted improvements in patient care resulting
from the first of these treatments in the clinic have stimulated further research on the role of integrins on other vascular
cells in these processes and in the search for new inhibitors. Both the development of specific inhibitors and of mice with
specific integrin subunit genes ablated have contributed to a better understanding of the function of integrins in development
of the cardiovascular system. 相似文献
17.
In addition to the relatively well established role of corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP)
in the mediation of the stress response, there is reason to believe that bombesin-like peptides (BN-LPs) may also contribute
to the mediation or integration of these responses and thus might be considered as putative 'stress peptides'. This review
provides evidence supporting this contention by showing that (i) BN-LPs are present at brain sites known to be activated by
stressors, (ii) stressor exposure alters utilization of BN-related peptides, (iii) exogenous BN administration mimics the
endocrine, autonomic and/or behavioral effects elicited by stressors, and (iv) antagonism of BN action attenuates the behavioral
and/or neurochemical effects of stressors or of exogenously administered peptide. The evidence presented also suggests that
BN-LPs mediate their stress-relevant effects through activation of CRH and/or AVP neurons. Several hypothetical mechanisms
for such peptidergic interactions are discussed as to the implications of considering BN-LPs as 'stress peptides'.
Received 16 July 2001; received after revision 27 August 2001; accepted 28 August 2001 相似文献
18.
Although originally identified as putative negative regulators of the cell cycle, recent studies have demonstrated that the
PHB proteins act as a chaperone in the assembly of subunits of mitochondrial respiratory chain complexes. The two PHB proteins,
Phb1p and Phb2p, are located in the mitochondrial inner membrane where they form a large complex that represents a novel type
of membrane-bound chaperone. On the basis of its native molecular weight, the PHB-complex should contain 12-14 copies of both
Phb1p and Phb2p. The PHB complex binds directly to newly synthesised mitochondrial translation products and stabilises them
against degradation by membrane-bound metalloproteases belonging to the family of mitochondrial triple-A proteins. Sequence
homology assigns Phb1p and Phb2p to a family of proteins which also contains stomatins, HflKC, flotillins and plant defence
proteins. However, to date only the bacterial HflKC proteins have been shown to possess a direct functional homology with
the PHB complex. Previously assigned actions of the PHB proteins, including roles in tumour suppression, cell cycle regulation,
immunoglobulin M receptor binding and apoptosis seem unlikely in view of any hard evidence in their support. Nevertheless,
because the proteins are probably indirectly involved in ageing and cancer, we assess their possible role in these processes.
Finally, we suggest that the original name for these proteins, the prohibitins, should be amended to reflect their roles as
proteins that hold badly formed subunits, thereby keeping the nomenclature already in use but altering its meaning to reflect
their true function more accurately.
Received 21 May 2001; received after revision 2 July 2001; accepted 24 July 2001 相似文献
19.
Neurotrophins are a family of structurally and functionally related neurotrophic factors which, in mammals, include: nerve
growth factor, brain-derived neurotrophic factor, neurotrophin-3 (NT-3), and NT-4/5. In addition to their canonical role in
promoting neuronal survival, these molecules appear to regulate multiple aspects of the development of the nervous system
in vertebrates, including neuronal differentiation, axon elongation and target innervation, among others. Actions of neurotrophins
and of their receptors in vivo are being analyzed by loss-of-function or gain-of-function experiments in mice. Here, we review
the phenotypes of the primary sensory system in these mutant mouse strains and the different strategies specifically involved
in the regulation of neuronal survival by neurotrophins in this portion of the nervous system.
Received 10 December 2001; received after revision 11 May 2002; accepted 13 May 2002
RID="*"
ID="*"Corresponding author. 相似文献
20.
Originally identified as a mediator of DNA damage response (DDR), checkpoint kinase 1 (Chk1) has a broader role in checkpoint activation in DDR and normal cell cycle regulation. Chk1 activation involves phosphorylation at conserved sites. However, recent work has identified a splice variant of Chk1, which may regulate Chk1 in both DDR and normal cell cycle via molecular interaction. Upon activation, Chk1 phosphorylates a variety of substrate proteins, resulting in the activation of DNA damage checkpoints, cell cycle arrest, DNA repair, and/or cell death. Chk1 and its related signaling may be an effective therapeutic target in diseases such as cancer. 相似文献
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